BCR/ABL oncogenic tyrosine kinase is present in most chronic myelogenous leukemias (CML) and a cohort of acute lymphocytic leukemias (ALL). Our previous studies indicated that BCR/ABL activates multiple signaling pathways responsible for the neoplastic phenotype of leukemic cells. SH2 and SH3 domains of BCR/ABL play an essential role in BCR/ABL-induced leukemogenesis. SH2 domain activates PI-3k/Akt pathway, and SH3 domain regulates integrins and affects adhesion, invasion and homing properties of leukemia cells. Both SH3 and SH2 domains of BCR/ABL regulate STAT5 activation, which seems to play an important role in protection from apoptosis, cell cycle progression, resistance to DNA damaging agents (cytostatic drugs) and leukemogenic transformation. Several downstream effectors of the BCR/ABL SH3+SH2 domains->STAT5 signaling pathway have been identified, which may contribute to these phenomena. The objective of this proposal is to further investigate the molecular mechanisms of BCR/ABL-mediated leukemogenesis in particular to identify and describe the functions of genes regulated by signaling from BCR/ABL SH3+SH2 domains->STAT5. In addition, the contribution of these signaling pathways to the blastic transformation of chronic myelogenous leukemia cells will also be examined.